Project summary Recent evidence shows that Alzheimer?s disease (AD) has etiological links to a number of metabolic disorders including type-2 diabetes (T2DM) with shared pathological processes including mitochondrial dysfunction and insulin resistance (IR). With respect to mechanisms underlying T2DM-associated systemic IR, there is overwhelming evidence for the role of ceramide (Cer), in particular C16-Cer generated from altered sphingolipid (SPL) metabolism. Our preliminary studies show increased levels of this ceramide species along with the enzyme that produces it i.e., ceramide synthase-6 (CerS6) in the hippocampus of a mouse model of AD, PDAPP Tg (J-20) as well as type-2 diabetic wild-type mice. These changes accompany increased levels of sphingosine 1-phosphate (S1P) thereby indicating an altered ?Cer/S1P rheostat? in AD. In this project, we will test the hypothesis that CerS6/C16-Cer upregulation is associated with brain IR and mitochondrial dysfunction in AD so that a blockade of this pathway will attenuate AD pathology and associated cognitive impairment. In addition, we will test the significance of ?Cer/S1P rheostat? down-stream of an adipokine receptor i.e., AdipoR activated by adiponectin (APN), which is known to counter IR in metabolic disorders and also to attenuate AD pathology in mouse models. To accomplish these exploratory objectives, we will use two mouse models of AD i.e., PDAPP Tg (J-20) and 5xFAD. The transgenic mice will be crossed with CerS6 knockout mice or administered CerS6 antisense oligonucleotides (Aim 1) or administered an APN agonist, AdipoRon (which is known to activate ceramidase and convert Cer into S1P as one of APN- mediated signaling pathways) with or without ceramidase deletion (Aim 2). This SPL pathobiology approach (an understudied area) will not only help gain a basic understanding of AD pathogenesis from a novel metabolism-centric perspective but also suggest lipid signaling based therapeutic strategies to treat AD.